1. Field of the Invention
This application relates to methods for prophylactic and therapeutic treatment of balance impairments. More particularly, the application relates to prevention or therapy of ototoxin-induced balance impairments by administration of neurotrophins.
2. Introduction
Balance impairments are serious handicaps which affect millions of people. Balance impairments can be attributed to a wide variety of causes, including infections, mechanical injury, loud sounds, aging, and chemical-induced ototoxicity that damage neurons and/or hair cells of the peripheral vestibular systems. Vestibular ganglion neurons (xe2x80x9cVGNxe2x80x9d), which are primary afferent sensory neurons responsible for balance, deliver signals from the utricle, saccule and ampullae of the inner ear to the brain through the eighth nerve connecting primary auditory neurons in the spiral ganglia to the brain stem. Damage to the peripheral auditory system is responsible for a majority of balance deficits (Dublin, 1976; Lim, 1986) with destruction of vestibular ganglia neurons as a major cause of balance impairments.
During embryogenesis, the vestibular ganglion, spiral ganglion, and the otic vesicle are derived from the same neurogenic ectoderm, the otic placode. The vestibular ganglion neurons send peripheral neuronal projections to hair cells of the inner ear and extend central projections to the brainstem nuclei. This system is sensitive to ototoxins that include therapeutic drugs, antineoplastic agents, contaminants in foods or medicines, and environmental and industrial pollutants. Ototoxic drugs include the widely used chemotherapeutic agent cisplatin and its analogs (Fleischman et al., 1975; Stadnicki et al., 1975; Nakai et aL, 1982; Berggren et al., 1990), commonly used aminoglycoside antibiotics, e.g. gentamicin, for the treatment of infections caused by Gram-negative bacteria, (Sera et al., 1987; Hinojosa and Lerner, 1987; Bareggi et al., 1990), quinine and its analogs, salicylate and its analogs, and loop-diuretics.
The toxic effects of these drugs on vestibular ganglion neurons are often the limiting factor for their therapeutic usefulness. For example, antibacterial aminoglycosides such as gentamicins, streptomycins, kanamycins, tobramycins, and the like are known to have serious toxicity, particularly ototoxicity and nephrotoxicity, which reduce the usefulness of such antimicrobial agents (see Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 6th ed., A. Goodman and Gilman et al., eds; Macmillan Publishing Co., Inc., New York, pp. 1169-71 (1980)). Aminoglycoside antibiotics are generally utilized as broad spectrum antimicrobials effective against, for example, gram-positive, gram-negative and acid-fast bacteria. Susceptible microorganisms include Escherichia spp., Haemohilus spp., Listeria spp., Pseudomonas spp., Nocardia spp., Yersinia spp., Klebsiella spp., Enterobacter spp., Salmonella spp., Staphyloccocus spp., Streptococcus spp., Mycobacteria spp., Shigella spp., and Serratia spp. Nonetheless, the aminoglycosides are used primarily to treat infections caused by gram-negative bacteria and, for instance, in combination with penicillins for the synergistic effects. As implied by the generic name for the family, all the aminoglycoside antibiotics contain aminosugars in glycosidic linkage. Ototoxicity is a dose-limiting side-effect of antibiotic administration. For example, nearly 75% of patients given 2 grams of streptomycin daily for 60 to 120 days displayed some vestibular impairment, whereas at 1 gram per day, the incidence decreased to 25% (U.S. Pat. No. 5,059,591). Ototoxicity is also a serious dose-limiting side-effect for cisplatin, a platinum coordination complex, that has proven effective on a variety of human cancers including testicular, ovarian, bladder, and head and neck cancer. Cisplatin damages vestibular systems (Fleischman et al., 1975; Stadnicki et al., 1975; Nakai et aL, 1982; Carenza et al., 1986; Sera et al., 1987; Hinojosa and Lerner, 1987; Bareggi et al., 1990).
Accordingly, there exists a need for means to prevent, reduce or treat the incidence and/or severity of ototoxin-induced balance impairment related to vestibular neurons, particularly that arising as an unwanted side-effect of ototoxic therapeutic drugs, which include cisplatin and its analogs and aminoglycoside antibiotics. In addition, there exits a need for methods that allow higher and thus more effective dosing with these ototoxicity-inducing balance-impairing therapeutic drugs by concomitantly preventing or reducing the ototoxic effects of these drugs. What is needed is a method that provides a safe, effective, and prolonged means for prophylactic or curative treatment of ototoxin-induced balance impairment. In addition there is needed a rapid, reliable, and facile system for testing the effects and mechanisms of ototoxins on balance in animals, including humans, and for testing the efficacy of therapeutics to prevent, reduce or treat these impairments. The present invention provides such methods and systems to achieve these goals and others as well.
The present invention results from the discovery disclosed herein that administration of certain neurotrophins can prevent or reduce gentamicin- and cisplatin-induced cell death of vestibular ganglion neurons in dissociated cell culture in a dose-dependent manner. When neurotrophins or other growth factors were added together with cisplatin or gentamicin to a VGN culture, VGNs were specifically protected by neurotrophin-4/5 (NT-4/5), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not by NGF or other growth factors, including epidermal growth factor (EGF), basic fibroblast growth factor (xcex2FGF), and insulin-like growth factor-1 (IGF-1). It is one object of the invention to provide a method for treating a mammal to prevent, reduce, or treat the incidence of or severity of an neuron-related balance impairment, particularly an ototoxin-induced or -inducible balance impairment, by administering to a mammal in need of such treatment a trkB or trkC agonist composition containing a prophylactically or therapeutically effective amount of trkB or trkc agonist. The trkB or trkC agonist is preferably a neurotrophin, more preferably NT-4/5, NT-3, or BDNF, and most preferably NT-4/5, or a functional fragment or derivative thereof, a chimeric neurotrophin, a pantropic neurotrophin, or a small molecule or antibody agonist thereof.
According to the method of this invention a composition of the invention can be administered at a suitable interval(s) either prior to, subsequent to, or substantially concurrently with the administration of or exposure to balance-impairment inducing neuronal damage, preferably ototoxin-induced or -inducible balance impairment. It is another object of the invention to provide a method for treating a mammal to prevent, reduce, or treat neuronal-damage-related balance impairments, preferably an ototoxin-induced balance impairment, by administering to a mammal in need of such treatment a composition containing a prophylactically or therapeutically effective amount of the trkB or trkC agonist in combination with a prophylactically or therapeutically effective amount of a second trkB or trkC agonist or an agent that acts synergistically or additively to enhance or 20 complement the prophylactic or therapeutic effect of the first trkB or trkC agonist.
It is another object of the invention to provide an improved composition containing an ototoxicity-reducing or -preventing effective amount of the trkB or trkC agonist in combination with an ototoxic balance-impairment inducing pharmaceutical drug for administration to a mammal. Such improved compositions can further contain a pharmaceutically acceptable carrier. The pharmaceutical composition will have lower ototoxicity than the ototoxic pharmaceutical alone, and preferably, have a higher dosage of the ototoxic pharmaceutical than typically used. Examples of such improved compositions include cisplatin or other ototoxic cancer agents or an aminoglycoside antibiotic(s) in combination with a trkB or trkC agonist.
Still further, the invention relates to the use in medicine of compositions of the invention in cases of bacterial infection. The present invention provides a solution to the art that has long sought a therapy and a medicament which can prevent, reduce or treat the ototoxic balance impairment effects currently associated with certain antibiotics, and particularly with the more popular and commonly used aminoglycoside antibiotics without sacrificing the antimicrobial effectiveness of the aminoglycosides.
Still further, the invention relates to the use in medicine of compositions of the invention in cases of cancer. The present invention provides a solution to the art that has long sought a therapy and a medicament which can prevent, reduce, or treat the ototoxic balance impairment effects currently associated with certain chemotherapeutics, and particularly with the more popular and commonly used cisplatin chemotherapeutics without sacrificing the antineoplastic effectiveness of cisplatin or its analogs.
Still further, the invention relates to the use in medicine of compositions of the invention in cases where diuretics are needed. The present invention provides a solution to the art that has long sought a therapy and a medicament which can prevent, reduce, or treat the ototoxic balance impairment effects currently associated with certain diuretics, and particular with the more popular and commonly used loop-diuretics, without sacrificing their diuretic effectiveness.
Finally, it is an object of the invention to provide a organotypic utricle explant culture system that allows reliable, rapid, and facile determination of the ototoxic effect of compounds and the prophylactic or therapeutic effect of candidate compositions and methods of the invention.
Additional objects and features of the invention will be apparent to those skilled in the art from the following detailed description and appended claims when taken in conjunction with the figures.